Common inspection deficiencies Microbiology Laboratories and Quality Assurance Emmett Broderick GMP Inspector, Manufacturing Quality Branch, TGA
Overview Quality Control M icrobiology in M edicine M anufacturing Compliance with GM P requirements Inspection Process Common inspection deficiencies Critical GM P deficiencies in QC M icrobiology CAPSIG - September 2018 1
Quality control microbiology Good laboratory practices in a microbiology laboratory consist of activities that depend on several principles: • Aseptic technique • Control of media • Control of test strains • Operation and control of equipment • Diligent recording and evaluation of data • Training of the laboratory staff USP <1117> Microbiological Best Laboratory Practices CAPSIG - September 2018 2
Training Cleaning M edia Validation Preparation Environmental M onitoring of Disinfectant testing Cleanrooms M icrobial monitoring M icrobiological QC of gases Evaluation of Product Microbiology Raw M aterials Laboratory testing investigations Sterilisation T est M ethod Validation Validation Personnel In-process M onitoring testing CAPSIG - September 2018 3
GMP requirements PIC/S cGMP - PE009-13 – Part I Chapter 1 Quality Control, Product Quality Review, QRM – Part I Chapter 2 Training – Part I Chapter 3 Premises & Equipment – Part I Chapter 4 Documentation – Part I Chapter 5 Production (Sampling & Contamination Control) – Part I Chapter 6 Quality Control – Part I Chapter 7 Outsourced Activities – Part II Manufacturing of active pharmaceutical ingredients – Annexes 1 , 2, 3, 7, 8, 9, 11 , 15 , 19 PIC/S cGMP - PE009-13 Annexes CAPSIG - September 2018 4
Therapeutic Goods Order No. 77 Pharmacopoeia Requirements for Objectionable Finished Products Organisms (Default Standard) • Route of administration • British • Sterile • Formulation • European • M ultidose • M ethod of application • Intended recipient • United States • Non-sterile • Use of immunosuppressive agents, corticosteroids • Presence of disease, wounds, organ damage CAPSIG - September 2018 5
Inspection process • Inspection Plan § Defines scope & used as inspection aide • Review evidence of GMP compliance § Record keeping and data integrity § Equipment and method suitability § Personnel qualification § Handling of OOS • Report deficiencies § Rated based on product quality & compliance risk - Critical, Major and Other § Supported by relevant clauses in cGMPs CAPSIG - September 2018 6
Inspection scope Environmental Sampling M edia Equipment Personnel Testing M onitoring • Calibration • Training • Technique • Preparation • Raw M aterials • Sampling Plan • Logbooks • Deviations • Records • QC Program • In-Process • M ethods • Storage • Validation • Resources • Storage • Finished • Excursions Product • Expiry • M aintenance • Hygiene • Hold Times • Trending • Stability • Personnel • Reporting M onitoring • OOS • M ethod Validation CAPSIG - September 2018 7
Common inspection deficiencies in laboratory practice • Training – Clause 2.10 – Clause 2.11 • Test Method Validation – Clause 6.15 – Annex 15 §22 • Culture media & lab reagents – Clause 6.21 – Clause 6.23 CAPSIG - September 2018 8
• OOS Management – Clause 1.4 (xiv) – Clause 1.8 (vii) – Clause 1.9 (vi) – Clause 4.29 • Environmental Monitoring – Clause 1.9 (i) – Clause 4.29 – Clause 6.7 (vi) • Data Integrity – Clause 6.7 CAPSIG - September 2018 9
Training The requirements of Clause 2.10 and 2.11 were not fully met. For example: a. The requirements for operator training in sterility testing were not prescribed by procedure . b. The current training process for operators undertaking sterility testing did not specifically address the techniques or nuances associated with the testing of the range of products tested for sterility by the organisation. c. The training documents reviewed in relation to endotoxin testing indicated that the initial test performed by the analyst on the 6/1/16 failed and a subsequent test on the 13/1/16 passed. The training record referred to the second (passed) result only, and there was no comment or explanation of the reason regarding the initial failed test . d. The manufacturer had not yet implemented a system in the QMS for the ongoing re- qualification for sterile gowning , and the actions to be taken in the event that gowning qualification requirements are not met. CAPSIG - September 2018 10
Test method validation The requirements of Clause 6.15 and Annex 15§22 that test methods should be validated were not met. • The current procedure for the validation of the sterility test stated that the validation was deemed successful if visible growth was detected with each organism. There was no instruction to ensure that the growth in the test-articles under validation was comparable to the growth in the positive control . • The first attempt at the sterility validation for XXXXX failed to recover A. brasiliensis , and the test was repeated without modification and passed. There was no detail within the report regarding the investigation of the initial failure and no evidence of any modification of the test prior to repeating the validation. • The method for the microbiological testing of filtered ethanol used in the aseptic sterility testing areas of the facility was not validated . CAPSIG - September 2018 11
Test method validation - continued • For PET testing of XXXXX, the initial test for the neutralisation validation for A. brasiliensis failed due to inadequate recovery of the organism and the test was repeated without modification and passed. There was no out-of-specification report, investigation or details of any modification of the test following the initial failure. • The validation instructions for bile-tolerant Gram negative bacteria test validation did not ensure that results were read at the shortest permissible incubation times ( Also refer to BP ) • There were no records relating to the maximum valid dilution determination for XXXXX kit testing. • The method for the microbiological assay of antibiotics for XXXXX from XXXXX required a primary solvent extraction prior to testing. The method used for the extraction for antibiotic testing had not been validated . CAPSIG - September 2018 12
Microbiological media The requirements of Clause 6.19 that special attention should be given to the quality of laboratory reagents and culture media was not fully met as evidenced by the following examples: a. There was no QC testing (growth promotion) performed on media received for the microbiological environmental monitoring of the facility. b. The QC of R2A agar used in the lab did not include a batch-batch comparison of microbial recoveries. c. Media used for environmental monitoring (HBA) was not sterilised (irradiated) prior to use in the grade A/B areas . In addition, there was no record of the pre-incubation of the HBA plates used in production as required by internal procedures. d. There was no routine QC testing performed on semi-solid media that had been melted by microwave . In addition, the microwave melting process was not clearly defined by procedure . e. The methods for the QC growth promotion testing of media were not in accordance with or equivalent to those specified by the British Pharmacopoeia : • The initial QC testing for all agars (both non-selective and selective) was stated to be performed by the ecometric method. However, the method was not appropriate for the QC testing of agars used for enumerative tests due to the fact that the inoculum was not <100cfu . CAPSIG - September 2018 13
OOS management • The procedure for microbial "out of specification" results permitted a single retest which if passed, would allow acceptance of the product. The company had not established a statistically valid re- sampling plan for retesting activities. • The company did not have a formal procedure in place to review and assess their products for the presence of objectionable organisms. • Water produced in the unqualified purified water system located at the XXXXX site was inappropriately approved for use at the XXXXX site. There was no investigation to determine the potential risk of microbial contamination on therapeutic products. ISPE Cleaning Validation and Contamination 14 Control Practices - May 2016
OOS investigation • Non-conformance report XXXX relating to a TNTC microbiological result for process water did not adequately investigate the contamination source. No microbial identification was performed on the TNTC sample Retesting • The XXXX Powder in OOS-XXXX was not appropriately handled. The retest result was accepted from a second contract laboratory but no root cause had been documented to invalidate the initial OOS results from the first contract laboratory. ISPE Cleaning Validation and Contamination 15 Control Practices - May 2016
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